Malignancies of B and T lymphocytes, termed non-Hodgkin leukemias and lymphomas (NHL), are among the most common cancers of adults. They develop when physiologic process of normal lymphoid cells are misdirected, leading to the activation of cancer-causing genes, termed oncogenes. We previously established that mice develop a spectrum of B cell lineage tumors with many parallels to similar human neoplasms. Our studies are directed first at determining how similar the tumors of the two species are so that we can understand how to develop better mouse models for human neoplasms. Relevant models would provide opportunities for understanding the mechanisms driving diseases as well as for developing new approaches to diagnosis, treatment and possibly prevention. Mechanisms known to contribute to tumor development in many species include activation of oncogenes, inhibition of tumor suppressor genes (TSG) and mutation of DNA repair genes. A second major purpose of our studies then is to determine if and how these mechanisms also contribute to mouse lymphoid cell lineage neoplasms. Finally, we believe the knowing how mutant or abnormally expressed genes contribute to tumorigenesis will direct us to important insights into how they contribute to normal T and B cell biology. These directions have led us to study a spectrum of mice that develop T or B cell lymphomas either spontaneously or following genetic manipulations that silence or aberrantly activate selected genes with much of the work being done in collaborations with scientists at the NIH and in academia. Oncogenic transformation of cells requires several mutations that lead to growth factor sufficiency and independence of growth suppressive effects. In humans, these mutations are often due to recurring chromosomal changes while in mice they are caused most often by mutagenic integrations of retroviral DNA into the genome. Studies of a large number of aging mice predisposed to B cell lymphomas highlighted candidate cancer genes in the Notch and NF-kB signaling pathways along with genes governing B cell lineage commitment. Recent studies have identified mutations in TRAF3, a component of the non-canonical NF-kB signaling pathway, in human diffuse large B cell lymphomas (DLBCL) and less frequently in other subsets of human NHL. To directly assess the importance of defective TRAF3 signaling to lymphoma development, we studied mice selectively deficient in TRAF3 in B cells. These mice developed a high incidence of lymphomas with similarities to splenic marginal zone and B-1a B cell lymphomas. p53, a TSG, is one of the most frequently mutated genes in human cancers including NHL. We previously reported that deletion of p53 in mice results in the development of early T cell lymphomas and a low incidence of splenic marginal zone lymphomas (MZL) that develop only after most mice have died of T cell neoplasms. Two new studies investigated the effects of selectively silencing p53 in B cells. The results showed that silencing of p53 was sufficient to trigger transformation of mature B cells that were pre-germinal center with most having histologic features of MZL. The long latencies for disease suggested that that p53-mediated disease initiation must be complemented by the accumulation of additional mutations for full transformation. B and T cells differ from all other somatic cells in thhat they develop physiologic single and double strand breaks (DSB) in DNA in order to generate immune receptors and diversify B cell antigen-binding avidity through somatic hypermutation (SHM) and function by class switch recombination (CSR). Both SHM and CSR are dependent on the activity of a single enzyme, AID (activation-induced cytidine deaminase) in germinal center (GC) B cells. Aberrant resolution of breaks formed during CSR can result in chromosomal translocations involving the IgH locus and Myc in human Burkitt lymphomas that activate Myc expression as a proximal event in transformation. Studies of a mouse model of endemic Burkitt lymphoma showed that Myc activation is associated with long range epigenetic effects of the 3 regulatory sequences of the IgH locus. What has not been clear is if distal regulatory elements within the IgH locus influence translocations involving Myc. Studies of mice bearing transgenes containing the IgH locus knocked into five different locations showed they could undergo rearrangements with Myc resulting in the development of plasmacytomas. Thus, the IgH region itself contains all the elements needed for both translocation and deregulation of Myc expression. The initiation and progression of lymphoid tumors is also influenced by chronic extracellular stimuli and the constitutive activation of intracellular signaling pathways that have been thought to synergize with signals driven by engagement of antigen-specific T or B cell receptors. ARF-BP1 has been identified as a ubiquitin E3 ligase that influences tumor development by inducing degradation of the tumor suppressor, p53, and stabilizing the transcriptional activity of Myc. Studies of mouse and human B lymphoma cell lines revealed that ARF-BP1 is part of a large intracellular protein complex comprised of ARF-BP1, ARF, p53, the Myc/Max heterodimer and CTCF, a multifunctional chromatin-binding protein involved in the transcriptional reglation of both p53 and Myc. The findings implicate ARF-BP1 as an important determinant of B cell homeostasis. Further studies are rquired to determine how how ARF-BP1 and its target proteins influence B cell development and function. Finally, we continue to be active in efforts to improve the classification systems for mouse hematopoietic neoplasms as they relate to similar human neoplasms. To do this, it is important for pathologists to be able to discriminate between hematopoietic neoplasms and non-malignant reactive lesions and we have developed guidelines for making these determinations.